Studies have been established to investigate the role of oncogenes in carcinogen-induced human tumors and the role of allelic variants of various candidate genes in cancer susceptibility. To investigate the role of oncogenes in chemical carcinogenesis, fixed tissue blocks have been obtained from 50 cases of benzidine or beta-naphthylamine associated bladder cancer, and 100 bladder cancer cases without such exposures. The polymerase chain reaction (PCR) is being used to amplify H-ras genes followed by oligonucleotide probing,and direct sequencing for oncogene activating mutations at codons 12, 13, and 61 , The pattern and mutational spectra of oncogene activation is being compared between benzidine/beta-- naphthylamine associated tumors and those which arose spontaneously. Fixed tissue samples of lung tumors have been obtained from individuals with primary lung cancers who had high dose occupational exposure to one of a variety of known lung carcinogens, including radon, asbestos, nickel, along with smoking-induced and non-smoking associated tumors. PCR with oligonucleotide probing and direct sequencing is being used to characterize K-ras gene mutations in adenocarcinomas, which will then be related to exposure status. Future plans for both bladder tumors and squamous cell lung tumors are to characterize deactivation of tumor suppressor genes, particularly p53, in relation to exposure. A case control study of bladder cancer is under way to investigate whether restriction fragment length polymorphisms of proto-oncogenes correlate with cancer susceptibility. Southern blots are being used to determine whether rare alleles of H-ras and other proto-oncogenes correlate with cancer susceptibility. In addition, PCR-based assays for other polymorphic candidate genes are being explored. A major goal is to investigate the interaction between genotype and environmental exposure in determining disease.